Cardiovascular autonomic dysfunctions and sleep disorders.

Accepted Manuscript Cardiovascular autonomic dysfunctions and sleep disorders Giovanna Calandra-Buonaura, Federica Provini, Pietro Guaraldi, Giuseppe Plazzi, Pietro Cortelli, Prof. PII:

S1087-0792(15)00075-1

DOI:

10.1016/j.smrv.2015.05.005

Reference:

YSMRV 885

To appear in:

Sleep Medicine Reviews

Received Date: 19 December 2014 Revised Date:

8 April 2015

Accepted Date: 25 May 2015

Please cite this article as: Calandra-Buonaura G, Provini F, Guaraldi P, Plazzi G, Cortelli P, Cardiovascular autonomic dysfunctions and sleep disorders, Sleep Medicine Reviews (2015), doi: 10.1016/j.smrv.2015.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Cardiovascular autonomic dysfunctions and sleep disorders

Giovanna Calandra-Buonaura a,b, Federica Provini a,b, Pietro Guaraldi c, Giuseppe

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Plazzi a,b, Pietro Cortelli a,b

a.

IRCCS, Institute of Neurological Sciences, Bellaria Hospital, Bologna, Italy

b.

Department of Biomedical and Neuromotor Sciences (DIBINEM), University of

Local Public Health Authority of Modena and Bologna, Italy

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c.

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Bologna, Bologna, Italy

Correspondence to: Prof. Pietro Cortelli

IRCCS, Institute of Neurological Sciences

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Department of Biomedical and Neuromotor Sciences, University of Bologna c/o Padiglione G, Ospedale Bellaria via Altura n°3, 40139 Bologna, Italy

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Tel: +39 0514966929; Fax: +39 051 4966176; Email: [email protected]

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Running Title: Cardiovascular dysautonomia and sleep disorders

Giovanna Calandra-Buonaura, Federica Provini, Pietro Guaraldi, Giuseppe Plazzi and Pietro Cortelli declare no conflict of interest related to this manuscript.

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ACCEPTED MANUSCRIPT Summary

Animal and human studies have shown that disorders of the autonomic nervous system may influence sleep physiology. Conversely, sleep disorders may be

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associated with autonomic dysfunction. The current review describes the clinical

presentation, supposed pathogenetic mechanisms and the diagnostic and prognostic implications of impaired cardiovascular autonomic control in sleep disorders. This

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dysfunction may result from a common pathogenetic mechanism affecting both

autonomic cardiovascular control and sleep, as in fatal familial insomnia, or it may be

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mainly caused by the sleep disorder, as observed in obstructive sleep apnoea. For other sleep disorders, like primary insomnia, restless legs syndrome, narcolepsy type 1 and rapid eye movement sleep behaviour disorder, the causal link with the autonomic dysfunction and its possible impact on health remains unsettled. Given its

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clinical implications, most of the data available suggest that a systematic assessment of the association between sleep disorders and impaired autonomic control of the cardiovascular system is warranted. Understanding the mechanism of this

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association may also yield insights into the interaction between the autonomic

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nervous system and sleep.

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Keywords: Autonomic Cardiovascular autonomic dysfunction

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Sleep disorder Fatal familial insomnia Obstructive sleep apnoea

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Primary insomnia Restless legs syndrome

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Narcolepsy

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Idiopathic REM sleep behaviour disorder

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ACCEPTED MANUSCRIPT Abbreviations ANS

autonomic nervous system

REM

rapid eye movement

BP

blood pressure

RLS

restless legs syndrome

BRS

baroreflex sensitivity

SBP

systolic BP

CPAP

continuous positive airway pressure

SCOPA-AUT

scales for outcomes in PD -

DBP

diastolic BP

EDS

excessive daytime sleepiness

FFI

fatal familial insomnia

HF

high frequency

HR

heart rate

HRV

heart rate variability

iRBD

idiopathic REM sleep behaviour disorder

LF

low frequency

MIBG

meta-iodo-benzylguanidine

MSNA

muscle sympathetic nerve activity

NREM

non-rapid eye movement

NT1

narcolepsy type 1

NTS

nucleus of the solitary tract

OH

orthostatic hypotension

OSA

obstructive sleep apnoea

PD

Parkinson disease

PI

primary insomnia

RBD

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PLMS

autonomic

periodic limb movements during sleep REM sleep behaviour disorder

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ACCEPTED MANUSCRIPT Introduction

The autonomic nervous system (ANS) regulates visceral functions (cardiovascular function, respiration, thermoregulation, neuroendocrine secretion, gastrointestinal,

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and genitourinary functions) and processes controlling vital functions in response to internal and external demands with the final aim of maintaining body homeostasis. The ANS exerts its control through several interconnected areas of the central

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nervous system belonging to the central autonomic network and two efferent

pathways, the sympathetic and parasympathetic NS composed of preganglionic

synapses with the target organs [1].

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neurons in the brain stem and spinal cord, and postganglionic neurons which form

ANS activity, including cardiovascular system control, is influenced by sleep and is modified in different sleep stages. Further, the neuronal populations participating in

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the transition from wake to sleep and in the subsequent development of the sleep stages are localized near to and reciprocally interconnected with the ANS areas involved in cardiovascular control [2,3].

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As a consequence, several general medical and neurologic disorders may cause cardiovascular autonomic dysfunction and sleep disturbances. Conversely, some

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sleep disorders [4] are associated with impaired autonomic control of the cardiovascular system, which may result in unbalanced sympathetic or parasympathetic modulation of the cardiovascular functions during sleep and wakefulness. This review aims to describe the clinical presentation, supposed pathogenetic mechanisms and the diagnostic and prognostic implications of cardiovascular autonomic dysfunctions associated with sleep disorders.

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ACCEPTED MANUSCRIPT This narrative review discusses only sleep disorders of the international classification of sleep disorders for which English language articles exploring the autonomic cardiovascular control in adults were available. Studies also had to be published by at least two different research groups using at least three of the methods reported

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below. The search was performed on Pubmed and other relevant databases inserting the names of the sleep disorders as keywords paired with the terms “autonomic”, “cardiac”, “cardiovascular”, “blood pressure”, “heart rate”, “sympathetic”, and

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“parasympathetic”. Reference lists of the identified articles were also searched for additional sources.

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These inclusion criteria served to limit the broad scope of the topic and to ensure sufficient data to form the basis of a discussion on the association between cardiovascular autonomic dysfunction and sleep disorders. As a result, impaired autonomic control of the cardiovascular system during sleep (as may occur in sudden

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unexpected death in epilepsy, nocturnal hypertension in patients with cardiovascular autonomic failure) is not discussed.

According to our literature search, the association between cardiovascular autonomic

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dysfunction and sleep disorders may result from a common pathogenetic mechanism affecting both the autonomic cardiovascular control and sleep as in fatal familial

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insomnia (FFI) or the autonomic dysfunction may be mainly caused by the sleep disorder, as observed in obstructive sleep apnoea (OSA). Alternatively, the causal link between the two conditions, for instance in primary insomnia (PI), restless legs syndrome (RLS), narcolepsy type 1 (NT1) and rapid eye movement (REM) sleep behaviour disorder (RBD) has not yet been clearly established [4]. Among the sleep disorders selected, we have reported all relevant articles on RLS, NT1, and RBD. The large number of articles available on OSAS and PI precluded

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ACCEPTED MANUSCRIPT inclusion of all papers, so a selection was made based on articles for and against the association in question when available, together with published reviews on the topic. The preliminary sections of the review address the neuroanatomical basis of cardiovascular autonomic control, the diagnostic procedures for the assessment of

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autonomic function integrity and the physiological modulation of cardiovascular

parameters during sleep. The paper then characterises the cardiovascular autonomic dysfunction associated with each of the selected sleep disorders, highlighting its

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impact on patient’s quality of life and the prognosis of the associated sleep disorder.

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Neuroanatomical basis of cardiovascular autonomic control

Physiologic control of the cardiovascular system results from a balance between sympathetic and parasympathetic activity regulated by the medullary reflexes and by

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descending influences from other areas of the central autonomic network. The medullary reflexes are triggered by activation of baroreceptors, cardiac receptors and chemoreceptors [2].

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The parasympathetic influence on the heart mediated by the vagus nerve through the neurotransmitter acetylcholine arises primarily from the nucleus ambiguus and leads

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to a decrease of heart rate (HR), atrio-ventricular conduction and ventricular excitability. Opposite effects are produced through the neurotransmitter norepinephrine by the sympathetic post-ganglionic neurons activated by the preganglionic sympathetic neurons located in the intermediolateral columns in the upper thoracic segments of the spinal cord [2]. The baroreceptor reflex, or baroreflex, is the most important mechanism involved in blood pressure (BP) control [5]. The arterial baroreceptors are mechanoreceptors

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ACCEPTED MANUSCRIPT mainly located in the carotid sinuses and aortic arch, innervated by the glossopharyngeal and vagus nerves, which respond to changes in carotid or aortic stretch elicited by rises or falls in arterial BP and provide inputs to the nucleus of the solitary tract (NTS) (Figure 1) [5]. Baroreflex activity is modulated by areas of the

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central autonomic network like the hypothalamus whose top-down inputs directed to the NTS contribute to short- and long-term BP control [5-7]. However, the NTS also has a bottom-up modulatory role exerted by its ascending projections to the upper

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brain. This reciprocal interaction suggests that changes in baroreflex afferent activity may influence the higher level of autonomic control, including the mechanisms

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adjusting the sleep–wake cycle [5-7].

Lastly, the arterial chemoreceptors in the carotid bodies and aortic arch also participate in the regulation of cardiovascular parameters. Hypoxia-induced stimulation of these chemoreceptors may lead to sympathetically mediated

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vasoconstriction resulting in a BP increase and vagally mediated HR decrease. This respiratory-cardiovascular interaction may be involved in the pathophysiology of

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harmful cardiovascular consequences like hypertension in OSA [8,9].

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Assessment of cardiovascular autonomic functions

Clinical manifestations of cardiovascular autonomic dysfunction include tachycardia, bradycardia, paroxysmal or sustained hypertension, and orthostatic hypotension (OH) [10], which is frequently associated with supine hypertension [11]. Diagnosis of cardiovascular autonomic dysfunction requires careful history-taking to disclose any mild symptoms concealed by compensatory mechanisms, and a detailed examination including evaluation of BP response to standing [11].

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ACCEPTED MANUSCRIPT Autonomic symptoms may be screened by questionnaires like the autonomic symptom profile [12] or the “scales for outcomes in Parkinson's disease – autonomic” (SCOPA-AUT) [13]. The autonomic symptom profile is a self-report questionnaire that explores nine symptom domains (orthostatic intolerance, reflex syncope, sexual

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failure in men, urinary and gastrointestinal symptoms, including gastroparesis,

constipation and diarrhoea, secretomotor, vasomotor and pupillomotor symptoms and sleep dysfunction) and provides an index of autonomic symptom severity with

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appropriate weighting, the composite autonomic symptoms score [12]. The SCOPAAUT is a 25-item questionnaire assessing gastrointestinal, urinary, cardiovascular,

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thermoregulatory, pupillomotor and sexual dysfunction in Parkinson disease (PD) and providing a score, ranging from 0 to 69, with the highest score reflecting worse autonomic functioning [13].

The functional assessment of ANS integrity frequently relies on indirect methods,

pathological stimuli [11].

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which measure the reflex responses of the target organs to physiological and

The cardiovascular reflex tests (head-up tilt test, Valsalva manoeuvre, handgrip,

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deep breathing and cold face) assess HR and BP changes in response to specific manoeuvres, disclosing a dysfunction of the autonomic control of the cardiovascular

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system and assessing the integrity of the parasympathetic and the sympathetic branch and baroreflex [11,14]. Blood samples can be collected to measure plasma catecholamines during the tests or over a 24-hour period. In certain disorders this may be of value to characterize the feature (e.g. overactivity or failure) and the site (e.g. preganglionic or postganglionic) of impaired sympathetic activity. Plasma noradrenaline provides a measure of sympathetic neural activity and plasma adrenalin of adrenal medullary activity [11].

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ACCEPTED MANUSCRIPT When an impairment of the physiological circadian variation of the cardiovascular parameters is suspected or autonomic disturbances present mainly during sleep, 24hour polygraphic recordings may serve to monitor the circadian fluctuations of these parameters and their changes in relation to different physiological states

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(wakefulness, non-rapid eye movement -NREM- and REM sleep) or degree of alertness.

Several indirect techniques have been applied to evaluate baroreflex function. In

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particular, the slope of the HR changes in response to BP changes evoked by these methods is commonly referred to as baroreflex sensitivity (BRS, ms/mmHg) [15].

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Spectral analysis of HR variability (HRV), calculated from the interval between two consecutive R-waves of QRS complexes in the ECG trace, is used to assess sympathetic or parasympathetic cardiac control. The power spectrum of HRV comprises high-frequency components (HF: 0.15–0.4 Hz), reflecting parasympathetic

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outflow and breathing activity, low frequency components (LF: 0.04–0.15 Hz), mediated mainly by sympathetic activity, and very low frequency components (0– 0.04 Hz). Even if the interpretation of the LF component as a pure marker of

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sympathetic activity remains controversial, the LF/HF ratio is used as a reliable indicator of sympathetic and parasympathetic balance [16].

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BP fluctuations, occurring within a 24-hour period (beat-to-beat, minute-to-minute, hour-to-hour, and day-to-night BP changes), i.e. very short-term and short-term BP variability or over more prolonged periods of time i.e. long-term BP variability, can also be computed by various methods (e.g. standard deviation of the mean BP values over a defined period, day-to-night variation, spectral analysis as for HR). These fluctuations are the result of a complex interaction between extrinsic environmental and behavioural factors and intrinsic cardiovascular regulatory

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ACCEPTED MANUSCRIPT mechanisms (neural central, neural reflex and humoral influences). Increased short and long term BP variability has been associated with the development of organ damage and an increased risk of cardiovascular events [17]. Muscle sympathetic nerve activity (MSNA) and skin sympathetic activity can be

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recorded by percutaneous insertion of tungsten microelectrodes into the peroneal or median nerve. MSNA supplies blood vessels and therefore exerts a vasoconstrictor effect, while sympathetic activity in skin nerve also supplies sweat glands. As muscle

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vasoconstriction is tightly coupled with arterial baroreceptors, MSNA is linked to the baroreflex, and the bursts of activity are generated during diastolic BP (DBP)

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reduction [18].

Finally, imaging studies with radioactive tracers may distinguish the central or postganglionic site of the autonomic lesion. For example, cardiac 123-meta-iodobenzylguanidine (MIBG) scintigraphy is used to assess cardiac sympathetic

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innervation which is impaired in post-ganglionic cardiovascular autonomic disorders [19].

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Physiological modulation of cardiovascular function during sleep

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Although the mechanisms linking cardiovascular changes to sleep states are not completely understood, sleep-related changes in cardiovascular function result from a complex integration between central autonomic influences and cardiovascular reflexes [3]. Sympathetic control of cardiovascular function progressively decreases from wakefulness to deep NREM sleep while parasympathetic tone remains dominant during most of the sleep period [20]. NREM sleep is characterised by a progressive

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ACCEPTED MANUSCRIPT BP and HR decrease, which becomes more pronounced from stage 1 to stage 3 NREM [21]. Healthy normotensive persons show a 10-20% BP decline during sleep compared to mean daytime values, a phenomenon referred to as “dipping”, while a non-dipper BP profile is defined as a BP reduction < 10% [22]. The baroreflex

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function is reset during NREM sleep and BRS increased, maintaining slow HR despite the BP decrease.

Further changes in EEG activity, with the appearance of EEG signs of cortical or

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subcortical arousal (intermittent alpha rhythm, K-complex sequences, and slow wave sequences), associated with increases in BP, HR, and ventilation occur periodically

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every 20 to 30 seconds during NREM sleep [23,24] or transiently as part of the physiological response to an arousing stimulus [7,25].

From NREM to REM sleep a progressive sympathetic predominance is observed associated with BP and HR values comparable with those during wakefulness. BRS

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differs in response to hypotensive and hypertensive stimuli and shows a non-uniform behaviour during REM occurring in different nocturnal sleep cycles [26]. Finally, transient HR and BP increases occur during REM sleep in association with sleep

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bursts of REMs and muscle twitches.

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A sleep disorder sharing the same pathogenetic mechanism as the cardiovascular autonomic dysfunction

Fatal familial insomnia

FFI is an autosomal-dominant prion disease linked to a missense mutation at codon 178 of the prion protein gene located on chromosome 20 co-segregating with

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ACCEPTED MANUSCRIPT methionine at codon 129, the site of a common methionine-valine polymorphism [2729]. A sporadic form of FI has also been described sharing clinical and neuropathological features with FFI [29]. The onset of FFI is in middle to late adulthood: symptoms begin, on average, at the

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age of 50 (between 36 and 62 years of age) [29]. However, onset in the twenties is possible [30]. Both sexes are equally affected. The earliest features of the disease include an inability to nap, difficulty falling asleep at night, and early awakening. At

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the same time, patients appear apathetic and drowsy. Autonomic signs may also occur early in the disease course and include a tendency to perspire, salivate and

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lacrimate, tachycardia, hypertension, urinary urgency, impotence and slight evening pyrexia. The disease is fatal and, from the onset of insomnia, death ensues after either a short ( 70 beats per minute) compared with men without sleep problems with HR values < 61 beats per minute [77].

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A significant HR increase in PI has not been consistently replicated in other studies [78-80]. However Spiegelhalder and coworkers [80] found that PI patients, despite

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comparable resting HR values, have a lower wake-to-sleep HR reduction compared to controls, which was shown previously to be an independent risk factor for cardiovascular diseases [81]. Spectral analysis of HRV demonstrated enhanced nocturnal sympathetic activity and reduced parasympathetic activity during sleep and night-time wakefulness in 12 PI patients compared to 12 controls [76]. On the contrary, another study did not disclose any differences in nocturnal HRV parameters between 14 PI patients and 14 controls

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ACCEPTED MANUSCRIPT [79]. Exploring the relationship between cardiac vagal influence and delta electroencephalographic power by means of coherence analysis, the same study found that the physiological interaction between changes in cardiac autonomic activity and delta power is altered in PI patients, suggesting that this finding might

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lead to increased cardiovascular risk [79]. Spiegelhalder and coworkers [80]

compared polysomographic recordings and nocturnal HR and HRV in 58 PI patients and 46 controls, finding significantly lower parasympathetic activity compared to

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controls only in PI patients with short sleep duration. Another two studies

investigating HRV parameters in small groups of PI patients during daytime did not

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observe any differences compared to controls [78,82].

Lanfranchi and colleagues [83] compared 24-hour BP values in 13 normotensive PI patients and 13 controls, reporting higher night-time systolic BP (SBP) and blunted day-to-night SBP dipping in the PI group. These results were not explained by

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differences in polysomonographic measures of poor sleep or indices of sleep fragmentation. However, in agreement with the hyperarousal model the blunted SBP fall was positively correlated with electroencephalographic indices of enhanced brain

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cortical activation (beta activity) during NREM sleep. Vgontzas and coworkers [84] used a cross-sectional design to investigate the

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association between hypertension and insomnia and polysomnographically determined sleep duration in 1741 participants. This study demonstrated that insomnia was linked to hypertension only in patients with PI and short sleep duration. By contrast, neither insomnia without short sleep duration nor short sleep duration without any sleep complaints were significantly associated with hypertension. In summary, despite accumulating evidence indicating that PI is associated with cardiovascular diseases, the aetiological mechanisms of this association remain

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ACCEPTED MANUSCRIPT unclear and data suggesting a sympathetic-vagal imbalance in PI have not been univocally replicated.

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Restless legs syndrome

RLS is a sensorimotor disorder characterised by an irresistible urge to move the legs usually associated with unpleasant sensations at the same site, occurring

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predominantly in the evening, worsening during periods of rest or inactivity and partially or totally relieved by movements [4]. The overall prevalence of RLS is

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around 3%. The wide prevalence variation previously reported in the literature mainly reflected differences in RLS diagnostic and severity criteria, population characteristics, and study population source, and could be overcome by the new diagnostic consensus criteria [85].

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Nearly 80% of RLS patients experienced periodic limb movements during sleep (PLMS), spontaneous stereotyped, brief and repetitive movements, frequently involving flexion of the toe, ankle, knee, and hip and sometimes the arms [4]. PLMS

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also occur in other sleep disorders and in healthy subjects mainly after the age of 40 years. Polygraphic recordings show that PLMS are frequently associated with

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electroencephalographic changes ranging from increased theta activity to cortical arousals, and always entail cardiovascular changes [86-90]. RLS is also associated with sleep impairment including longer sleep latency, shorter sleep duration, higher prevalence of insomnia, poor sleep quality and increased daytime sleepiness [91]. A significantly positive correlation between RLS and cardiovascular diseases has been demonstrated in several large population-based cross-sectional studies [92]. This association proved stronger in patients with more frequent and/or severe RLS

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ACCEPTED MANUSCRIPT symptoms, while it does not seem correlated to diurnal hypertension [93,94]. Instead, the relationship between RLS and hypertension remains controversial [92,95]. Studies exploring this issue have recently been reviewed and a positive association was observed in 10 out of 17 studies [92]. Contradictory results may be explained by

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differences in study population and criteria for RLS and hypertension assessment, and certain medications used for RLS, which can lower BP values (e.g. clonidine). The increased cardiovascular risk and supposed correlation with hypertension in RLS

system towards a sympathetic predominance.

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may be the consequence of an impaired autonomic control of the cardiovascular

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Only one study investigated autonomic function in RLS patients by means of cardiovascular reflex tests and spectral analysis of HRV during wakefulness. This study found a significant increase in SBP values, which did not reach the level for a diagnosis of hypertension, in supine rest condition in 12 RLS patients compared to

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14 controls, associated with a tendency toward reduced amplitude of both sympathetic and parasympathetic response to head-up tilt test and blunted parasympathetic drive to BP changes. Despite the small sample of patients, this

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study suggests an ANS impairment during wakefulness in RLS [96]. A sympathetic-vagal imbalance in RLS may be induced by frequent autonomic

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arousals entailed by PLMS or sleep impairment [88-90,92,97]. Several studies demonstrated that PLMS are associated with repetitive significant increases in HR, SBP and DBP [86-90], which occur irrespectively of concomitant cortical arousal, despite being potentiated by cortical activation [86,88,89]. HR changes were higher in bilateral than unilateral PLMS [98] and BP changes increased with RLS disease duration and patient’s age [88]. Further, PLMS-related HR and BP increases were disclosed by nocturnal videopolysomnography also in healthy subjects enrolled as

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ACCEPTED MANUSCRIPT controls in two studies on RLS patients [90,99]. However, these HR and BP changes were less pronounced than in RLS patients. Spectral analysis of HRV confirmed an increased sympathetic-vagal balance associated with PLMS, which was more pronounced than those accompanying other sleep-related movements [100].

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Figure 3A shows the phasic periodic electroencephalographic and autonomic

sympathetic activations (HR and BP surges) associated with PLMS recorded in one of our patients with RLS. Similarly to what was previously described for OSA, these

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repetitive increases in sympathetic activity may progressively lead to a persistent increased sympathetic tone in RLS patients who show more pronounced PLMS-

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related cardiovascular changes compared to healthy subjects. The increased sympathetic tone may in turn be responsible for the increased cardiovascular risk and hypertension in this population.

However, several studies also demonstrated that cardiovascular changes usually

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herald by seconds the motor onset of PLMS [87,100], weakening the hypothesis that PLMS per se may cause impaired autonomic cardiovascular control in RLS. Further oscillations of EEG activity, systemic and pulmonary arterial pressure, HR, ventilation

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and muscle tone occur spontaneously during NREM sleep irrespective of movements [23,24]. Alternatively, increased sympathetic modulation and RLS might share the

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same pathophysiological mechanism involving an impairment of the descending inhibitory dopaminergic pathway projecting from the hypothalamus to the spinal dorsal and ventral horns and also to the intermediolateral cell columns of the spinal cord where the preganglionic sympathetic neurons are located [101]. According to this hypothesis, Manconi and colleagues [99] demonstrated that treatment with the dopamine agonist pramipexole decreased both the number of PLMS and the PLMS-related HR response in RLS patients. However, the study failed

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ACCEPTED MANUSCRIPT to demonstrate differences in basal sympathetic-vagal balance during NREM sleep stage 2 between 23 RLS patients and 10 control subjects, although age differences between patients and controls and the degree of RLS severity may explain the result of the study [99].

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Reduced sleep quantity and quality may also mediate the effect of RLS on

cardiovascular risk through increased sympathetic cardiovascular modulation.

According to this hypothesis, 24-hour monitoring in one RLS patient recorded a

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blunted nocturnal HR decrease and absence of physiological nocturnal SBP and DBP dip associated with sleep fragmentation (Figure 3B).

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The association between short sleep duration and increased cardiovascular risk, particularly coronary heart disease and stroke, has been demonstrated in both crosssectional and prospective studies. The quality of sleep for people sleeping ≤ 6 hours is an additional risk for cardiovascular diseases [102].

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Short-term sleep deprivation studies demonstrated SBP, DBP and HR increase the day after a sleep-deprived night associated with a significant increase in plasma and urinary catecholamine levels and LF/HF ratio, suggesting that sleep deprivation leads

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to a sympathetic-parasympathetic imbalance, with a prevalence of sympathetic modulation [103-105].

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However Kato and coworkers [106] demonstrated a significantly higher resting BP increase associated with lower MSNA activity and comparable HR values and plasma catecholamines in eight healthy subjects on the morning after a night of sleep deprivation compared to a morning after a night of normal sleep. These results were confirmed by a subsequent study which showed increased DBP values after 24-hour sleep deprivation and decreased MSNA activity, suggesting that the pressor response of sleep deprivation does not seem to be mediated by an increased

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ACCEPTED MANUSCRIPT sympathetic drive [106,107]. A resetting of the arterial baroreflex toward a higher BP level has been proposed as an alternative mechanism mediating the BP increase after sleep deprivation [107]. In summary, RLS has been significantly associated with an increased cardiovascular

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risk, but neither the association with hypertension or with a prevalence of

cardiovascular sympathetic modulation have been systematically demonstrated. The RLS-related increased cardiovascular risk might therefore not be the consequence of

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an impaired autonomic cardiovascular control due to PLMS or sleep disruption, but may be related to the frequent association between RLS and other cardiovascular

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risk factors (e.g. increased body mass index, diabetes, hypercholesterolaemia, smoking) [108-110].

Studies exploring the 24-hour and state-dependent sympathetic-vagal modulation and cardiovascular changes are necessary to confirm an impaired autonomic

risk.

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Narcolepsy type 1

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cardiovascular modulation in RLS and its relation with the increased cardiovascular

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NT1 is a sleep disorder characterised by excessive daytime sleepiness and signs of REM sleep dissociation, the most specific of which is cataplexy [4]. The disease is caused by a deficiency of orexin (hypocretin) signalling due to loss of neurons of the lateral and posterior hypothalamus releasing orexin peptides. These neuropeptides are implicated in the physiological functions (arousal, energy homeostasis, feeding, thermoregulation and neuroendocrine and cardiovascular control) mediated by changes in the ANS activity through multiple connections between orexin neurons

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ACCEPTED MANUSCRIPT and cerebral areas involved in central autonomic control [111]. Low or undetectable levels of hypocretin-1 are found in the cerebrospinal fluid of most NT1 patients. Autonomic dysfunctions in NT1 patients [112] include abnormal pupillometry function, erectile dysfunction, and impaired autonomic control of the cardiovascular system

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during sleep and wakefulness.

The nature of the cardiovascular autonomic dysfunction is controversial as the

sympathetic-vagal balance has been reported to be increased, decreased or normal

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with further differences during wakefulness and sleep (Table S2). Conflicting effects of orexins on the cardiovascular system have also been gathered from animal

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models. Intracerebroventricular microinjections of orexin in conscious rats enhanced sympathetic output causing HR and BP increases [113,114]. Similarly orexinknockout or orexin neuron-depleted mice showed significant basal hypotension and an attenuated sympathoexcitatory response to stress with respect to control mice,

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differences which were abolished by alpha-adrenergic or ganglionic blockade [115,116]. However, other, models of orexin-deficient mice did not show any differences in BP values compared to controls during wakefulness and demonstrated

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a blunted decrease in BP on passing from wakefulness to NREM sleep and an enhanced increase in BP on passing from NREM to REM sleep [117,118]. These

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studies suggest that lack of hypocretin in animal models does not necessarily reduce the sympathetic-vagal balance and may entail BP consequences varying among wake-sleep states. Interestingly, these studies also showed an increase in HR during sleep in narcoleptic mice, which was most evident in knockout mice with complete deficiency of hypocretin peptides [117,118]. Moreover, the night-time non-dipper BP profile did not produce subclinical hypertensive organ damage to the heart and kidney evaluated through histological and ultrastructural analysis of cardiovascular

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ACCEPTED MANUSCRIPT and renal tissue in these animal models [118], whereas it is known to increase cardiovascular risk irrespective of diurnal hypertension in humans [119]. Grimaldi and colleagues [120] first demonstrated a similar BP profile during wake and sleep in ten drug-free NT1 patients by means of 24-hour beat-to-beat BP, HR and

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wake-sleep cycle monitoring. Patients showed daytime SBP and DBP values

comparable to 12 controls, but a blunted decrease in nocturnal SBP and DBP. The state-dependent analysis of BP changes showed a significant pressure effect on SBP

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during night-time REM sleep, characterised by significantly higher SBP values in NT1 patients during REM, while SBP values during NREM sleep and DBP values during

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both NREM and REM sleep were similar to controls. Interestingly 24-hour HR values were significantly higher in NT1 patients but unlike BP modulation, day-night and state-dependent HR modulation were preserved, inducing HR variations comparable to those of the control group.

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A further study using 24-hour ambulatory BP monitoring found a higher percentage of non-dipper DBP in a sample of 36 NT1 patients compared to 42 controls (30% vs 3%) [121]. The diastolic non-dipper profile was negatively correlated with the

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percentage of REM sleep. Daytime SBP and DBP were not significantly different in the two groups, while daytime HR values were slightly but not significantly lower in

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NT1 patients.

A non-dipper profile points to an increased sympathetic-vagal balance during sleep in NT1 patients which may be due to either sympathetic prevalence or parasympathetic withdrawal. However, skin sympathetic activity and MSNA were normal in 13 NT1 patients during NREM and REM sleep, although these patients showed a non-dipper BP profile [122].

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ACCEPTED MANUSCRIPT A study on nine male NT1 patients compared with nine healthy subjects provided evidence that central autonomic control of the heart is enhanced during NREM sleep in NT1 patients, possibly as a result of an increased PLMS index [123]. Nonetheless, an attenuated HR response to PLMS was observed in 14 NT1 patients suggesting a

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lower sympathetic response related to hypocretin-deficiency [124]. Similar results were obtained in NT1 in relation to leg movements and arousal from sleep defined according to standard criteria [125-127]. The attenuated HR response was primarily

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predicted by hypocretin-deficiency. However the baseline HR values during sleep of the NT1 group in this study [125] were significantly elevated compared with controls,

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suggesting that the attenuated phasic HR increase may also be explained by the already elevated basal HR values resulting from a tonic sympathetic prevalence during sleep.

A continuously elevated HR in NT1 patients compared to controls was recently

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confirmed throughout sleep states and during wakefulness prior to sleep [128]. This HR increase was independent of sleep stage duration and sleep fragmentation, suggesting a direct effect of hypocretin deficiency. Further, the same study observed

[128].

EP

a blunted HR increase in response to awakening from NREM sleep in the NT1 group

AC C

Studies investigating autonomic cardiovascular control during wakefulness in NT1 patients also obtained conflicting results. Fronczek and colleagues found a higher increase in the total power spectrum of HR and BP variability in NT1 patients compared to controls in the supine awake condition, associated with a comparable LF/HF ratio of the HR variability, and hypothesized a reduced sympathetic tone [129]. However, HR was comparable in the two groups and therefore not readily compatible with a reduced sympathetic outflow. Moreover, normal very short-term BP variability,

31

ACCEPTED MANUSCRIPT calculated as standard deviation of the respective beat-to-beat values over a five minute window, and reduced cardiac BRS and cardiac vagal modulation were reported during wakefulness before sleep in a different study on NT1 patients [123]. A recent study found lower diurnal resting MSNA associated with lower HR and DBP

RI PT

values in NT1 patients compared to controls, suggesting a decreased sympathetic tone. Both MSNA and HR values were correlated to hypocretin values in line with a direct effect of hypocretin on autonomic regulation [130]. On the contrary, another

SC

two studies using HRV found increased sympathetic-vagal balance during

wakefulness preceding sleep [131] and an enhanced sympathetic activity at rest

M AN U

[132] in NT1 patients compared to controls.

In summary, NT1 patients may show a nocturnal non-dipper BP profile and impaired autonomic control of the cardiovascular system. As the direction of the cardiovascular autonomic impairment is not univocally ascertained, further studies to

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clarify this topic comparing different methodological approaches are required to better define the possible influence of this autonomic dysfunction on the

EP

cardiovascular risk in NT1 population.

AC C

REM sleep behaviour disorder

RBD is a REM sleep parasomnia characterised by abnormal dream-enacting behaviours emerging during REM sleep, often violent and injurious, and associated with a loss of physiological REM muscle atonia [4]. This condition may be idiopathic (iRBD) or associated with another neurologic disorder, mainly the neurodegenerative disorders named alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy) characterised by a parkinsonian syndrome in combination with other

32

ACCEPTED MANUSCRIPT motor signs, autonomic signs (cardiovascular autonomic failure, sexual dysfunction, neurogenic bladder and bowel) or cognitive impairment. The onset of RBD often precedes the clinical onset of the alpha-synucleinopathy by years [133-135]. As a result, several studies have tried to disclose markers predictive of the future

RI PT

development of these diseases in iRBD patients. A dysfunction in the autonomic

control of the cardiovascular system has been observed in iRBD. Mahowald and

Schenck [136] first reported lack of HR increase in association with the vigorous RBD

SC

behaviours. A subsequent study demonstrated that HR acceleration induced by

spontaneous body movements was blunted during both REM and NREM sleep in

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iRBD patients compared to controls [137]. These patients also showed impairment in one or more cardiovascular reflex tests assessing both sympathetic and parasympathetic functions during wakefulness [137]. A blunted HR increase associated with PLMS was later observed in iRBD patients compared to patients with

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RLS [138]. Similarly, a blunted HR increase in response to arousal and leg movements during sleep was found in iRBD patients compared to controls [139]. Interestingly, the HR response of iRBD patients was intermediate with respect to a

EP

control group and a group of PD patients presenting the lowest HR response to arousal and leg movements [139]. Finally, iRBD patients do not show the

AC C

physiological parasympathetic withdrawal and sympathetic prevalence observed on passing from NREM to REM sleep [140]. A recent study using SCOPA-AUT [13] found that iRBD patients compared to controls complained of significantly more autonomic symptoms, including symptoms suggestive of OH, the hallmark of sympathetic failure [141]. All these studies demonstrated that iRBD is associated with a dysfunction of cardiovascular autonomic control mainly due to an impairment of the sympathetic branch as occurs in alpha-synucleinopathies. However, whether this

33

ACCEPTED MANUSCRIPT dysfunction in iRBD predicts the development of a neurodegenerative disease is controversial. Frauscher and colleagues [142] evaluated 15 iRBD patients and an equal number of PD patients and healthy controls with cardiovascular autonomic function testing and the composite autonomic symptoms score [12], demonstrating

RI PT

autonomic dysfunction in iRBD patients of an intermediate degree between controls and PD patients. The authors suggested that iRBD patients with autonomic

dysfunctions might be at particular risk for developing an alpha-synucleinopathy.

SC

However, subsequent studies reached different conclusions. An impairment of

cardiac autonomic control evaluated through HRV was observed in patients initially

M AN U

diagnosed with iRBD, however the degree of this dysfunction did not differ between iRBD patients who subsequently did or did not develop a neurodegenerative disease [143]. Further, PD patients with RBD presented dysfunctions of cardiac autonomic control while PD patients without RBD behaved similarly to controls, suggesting that

TE D

RBD predicts cardiac autonomic dysfunction better than the presence of PD [144,145]. Consistently with these data, Kashihara and coauthors [146] demonstrated that MIBG uptake, a marker of cardiac sympathetic innervations, is more markedly

EP

reduced in iRBD than PD patients at an early disease stage, suggesting that this dysfunction seems integrally related to the pathogenesis of RBD rather than a

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preclinical sign of a specific neurodegenerative disease. The importance of finding early markers of neurodegenerative disease implies that systematic prospective autonomic investigations including cardiovascular autonomic testing are required in iRBD patients to better clarify the association between cardiovascular autonomic dysfunctions and RBD and its predictive role in the early diagnosis of neurodegenerative diseases.

34

ACCEPTED MANUSCRIPT Further, diagnosis of autonomic dysfunction in iRBD has clinical implications as autonomic symptoms, like syncope due to OH, can be treated with appropriate medications.

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Conclusions

Many animal and human studies have demonstrated the bidirectional interactions

SC

between sleep and ANS also showing that autonomic disorders may influence the physiology of sleep, and conversely sleep disorders may affect ANS functions. In

M AN U

particular, sleep disorders may be associated with impaired cardiovascular autonomic control which is one of the mechanisms implicated in the link between these disorders and an increased risk of developing cardiovascular diseases. However, neither impaired cardiovascular modulation nor its impact on the diagnosis

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and prognosis of sleep disorders have been systematically investigated and data on this association have not been univocally replicated. Overall it is likely that the sleep disorders described in this review are associated with

EP

different degrees of cardiovascular autonomic impairment which may not only affect patients’ quality of life, but may also have a negative impact on the prognosis of the

AC C

associated sleep disorder and may represent a risk factor for the development of other chronic diseases or life-threatening events. Consequently, studies exploring the 24-hour and state-dependent sympathetic-parasympathetic balance and cardiovascular changes are warranted.

Summary Point 1 Introduction

35

ACCEPTED MANUSCRIPT •

Cardiovascular function is continuously modulated by areas of the central nervous system acting through the sympathetic and parasympathetic nervous system.

•

The arterial baroreceptor and chemoreceptor reflexes may play an important

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role in the pathophysiology of harmful cardiovascular consequences like hypertension in obstructive sleep apnoea.

Impairment of cardiovascular autonomic control results in a sympatheticvagal balance increase or decrease.

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Summary point 2 Fatal familial insomnia •

SC

•

The clinical hallmark of fatal familial insomnia is agrypnia excitata syndrome characterised by a progressive sleep loss associated with oneiric stupor and

•

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autonomic sympathetic overactivation.

Impaired sympathetic-parasympathetic control of the cardiovascular system leads to a 24-hour increase in heart rate and blood pressure values and

Agrypnia excitata is due to a disruption of the thalamo-limbic circuits and is

AC C

•

EP

reduction of the nocturnal dip in blood pressure.

shared by other diseases in which these circuits are impaired.

Summary Point 3

Obstructive sleep apnoea •

Sympathetic overactivity and reduced baroreflex sensitivity have been demonstrated in obstructive sleep apnoea and play a prominent role in the development of cardiovascular diseases.

36

ACCEPTED MANUSCRIPT •

A correlation between reduced baroreflex sensitivity and excessive daytime sleepiness has been observed in obstructive sleep apnoea. Assessment of excessive daytime sleepiness may have an impact on the diagnosis or prevention of cardiovascular complications. Treatment of obstructive sleep apnoea with continuous positive airway

RI PT

•

pressure reduces daytime sympathetic overactivity and lowers blood pressure values in hypertensive patients while its effect on preventing cardiac

M AN U

Summary Point 4 Primary insomnia •

SC

arrhythmias is undetermined.

A growing body of evidence suggests that primary insomnia is a risk factor for developing cardiovascular diseases and adverse cardiovascular events. Increased sympathetic cardiovascular modulation has been observed in

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•

primary insomnia, but these findings have not been univocally replicated.

EP

Summary Point 5

•

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Restless legs syndrome

A positive correlation between restless legs syndrome and cardiovascular

diseases has been demonstrated in several population-based cross-sectional studies, while the association with hypertension is controversial.

•

Increased cardiovascular sympathetic modulation, although not yet systematically demonstrated, has been hypothesized as one of the aetiological mechanisms linking restless legs syndrome and increased cardiovascular risk.

37

ACCEPTED MANUSCRIPT Summary point 6 Narcolepsy type 1 •

Narcolepsy type 1 is caused by a deficiency of orexins probably involved in the modulation of cardiovascular autonomic control. Patients with narcolepsy type 1 may present a night-time non-dipper blood

RI PT

•

pressure profile which increases cardiovascular risk in humans. •

The sympathetic-parasympathetic balance is reported to be increased,

Summary point 7 REM sleep behaviour disorder •

M AN U

SC

decreased or normal during sleep and wakefulness in narcolepsy type 1.

REM sleep behaviour disorder may be idiopathic or associated mainly with the alpha-synucleinopathies, preceding the clinical onset of these diseases by

•

TE D

years.

Patients with idiopathic REM sleep behaviour disorder may show a failure of the sympathetic nervous system, as observed in alpha-synucleinopathies. Whether this autonomic dysfunction predicts the development of an alpha-

EP

•

AC C

synucleinopathy or is related to the pathogenesis of idiopathic REM sleep behaviour disorder is controversial.

Research agenda

1) The association between sleep disorders and impaired autonomic control of the cardiovascular system needs to be systematically assessed for its important clinical implications.

38

ACCEPTED MANUSCRIPT 2) Studies exploring the 24-hour and state-dependent sympatheticparasympathetic modulation and cardiovascular changes are required in the sleep disorders discussed. 3) The impact of a cardiovascular autonomic dysfunction on the prognosis of the

RI PT

associated sleep disorder should be addressed in prospective, interventional studies.

4) Cardiovascular autonomic dysfunctions in idiopathic REM sleep behaviour

synucleinopathies have to be defined.

SC

disorder and their predictive role in the early diagnosis of alpha-

M AN U

5) Understanding the mechanism underlying the association between cardiovascular autonomic dysfunction and sleep disorders may yield new

AC C

EP

TE D

insights into the interaction between autonomic nervous system and sleep.

39

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Legend to figures

Figure 1. Baroreflex. The baroreceptors activated by a blood pressure increase

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provide excitatory input to the nucleus of the solitary tract (NTS) which inhibits the sympathoexcitatory neurons of the rostral ventro-lateral medulla (RVLM) through

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activation of the inhibitory neurons of the caudal VLM (CVLM) and activates vagal pregaglionic neurons in the nucleus ambiguus (NAmb). The result is a decrease in sympathetic vasoconstrictor output leading to total peripheral resistance decrease and an increase in cardiac parasympathetic control leading to heart rate decrease, with a subsequent reduction of venous return to the heart and cardiac output. The baroreflex also inhibits vasopressin release by the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus.

63

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Figure 2. Sympathetic overactivity in fatal familial insomnia (FFI). 24-hour recordings in a patient with FFI (grey circles) showed a persistent increase in heart rate, mean arterial pressure, norepinephrine and cortisol levels compared to an age-

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matched control (white diamonds). The black bar indicates the dark period (b/m=beats/minute; ng/L=nanogram/liter; pg/ml=picogram/milliliter) [33].

SC

Figure 3. Two hypothesized mechanisms linking restless legs syndrome with increased cardiovascular risk. A) Periodic limb movements (PLM) during sleep are

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associated with periodic electroencephalographic (CZ) and autonomic activations (heart rate-HR- and blood pressure-BP- surges) which may cause sleep fragmentation and an increased sympathetic tone during sleep; B) The reduced sleep quantity and quality observed in restless legs syndrome may cause a blunted

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nocturnal HR decrease and absence of the nocturnal systolic BP (SBP) and diastolic BP (DBP) dip as shown during 24-hour recordings. The grey box indicates the dark period (b/m=beats/minute; ECG = electrocardiogram; N1 = non rapid eye movement

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sleep (NREM) stage 1; N2 = NREM stage 2; N3 = NREM stage 3; R = right; REM = rapid eye movement sleep; s = seconds; T-A resp = thoracic-abdominal respirogram;

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Tib ant = tibialis anterior muscle; W = wake).

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Table S1.

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Summary of articles included within the review on the association between obstructive sleep apnoea syndrome and cardiovascular autonomic dysfunction. Abbreviations: BP: blood pressure; BRS baroreflex sensitivity; ctrls: controls; CPAP: continuous positive airway pressure; DBP: diastolic BP; ECG: electrocardiogram; HF: high frequency; HR: heart rate; HRV: HR variability; LF: low frequency; MSNA: muscle sympathetic nerve activity; NA: noradrenaline;

Subjects

Measures

Results

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Author

SC

NE: norepinephrine; OSA: obstructive sleep apnoea syndrome; PSG: polysomnography; pts: patients; SBP: systolic BP; VPSG: video-polysomnography.

Conclusions

Carlson JT

6 normotensive

During supine rest: MSNA, intra-arterial

MSNA and plasma NE were significantly

The study demonstrated increased

et al.

OSA pts;

BP, arterial and venous plasma NE.

higher in OSA pts compared to ctrls with

sympathetic activity during

(1993) [48]

5 hypertensive

no difference between normotensive and

wakefulness in OSA pts.

hypertensive pts. SBP was positively related to resting MSNA.

5 OSA pts;

During nocturnal VPSG: continuous

All pts showed an increase in pulmonary


C et al.

5 hypertensive

recording of HR, systemic BP and

arterial pressure, acidosis, hypercapnia

sympathetic activity in relation to the

(1972) [40]

OSA pts

pulmonary arterial pressure. Blood

and hypoxia and rises in systemic arterial

apnoeic events.

BP and HR related to the apnoeic events.

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Coccagna

AC C

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OSA pts; 9 ctrls

samples for gas analysis were also collected. Cortelli P et

21 normotensive

During cardiovascular reflex tests the

OSA pts showed higher HR and NA

The study demonstrated sympathetic

al.

OSA pts; 20 ctrls

morning after a nocturnal VPSG:

plasma levels at rest and increased BP

overactivity and decreased BRS in

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continuous recording of HR, SBP, DBP

response to head-up tilt test compared to

normotensive awake OSA pts

and respiratory rate; plasma NA and

ctrls. BRS index during the Valsalva

compared to ctrls. The decreased

adrenaline before and during head-up tilt

manoeuvre was significantly lower in OSA

BRS in OSA pts might contribute to

test; BRS index during the Valsalva

pts.

the genesis of cardiac arrhythmias.

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(1994) [45]

SC

manoeuvre. 8 hypertensive

Urine specimens collected during sleep

NE and normethanephrine were


et al.

OSA men; 5

and wakefulness: urinary epinephrine,

significantly higher in OSA pts before

sympathetic activity in OSA

(1987) [47]

hypertensive ctrls

NE, metanephrine and

tracheostomy compared to ctrls and to

normethanephrine before and after tracheostomy in OSA. 6 OSA pts; 6 ctrls

During sleep and wakefulness: MSNA.

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Hedner J et

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Fletcher EC

al.

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(1988) [8]

18 OSA pts (8

HRV from 24-hour ECG recoding: LF,

al.

mild OSA and 10

HF and LF/HF.

(1998) [46]

severe OSA); 10 ctrls

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Noda A et

hypertensive pts throughout the day.

their own values after tracheostomy.

MSNA was increased in OSA pts


compared to ctrls during wakefulness.

sympathetic activity during the

MSNA increased during the apnoeic event

apnoeic event and during

and returned to baseline after the event.

wakefulness in OSA pts.

From 4 A.M. to 12 noon: the mean HF

Analysis of circadian HRV variations

value was significantly lower and the

showed an enhanced sympathetic

mean LF/HF value significantly higher in

modulation from morning to noon in

severe OSA pts compared to mild OSA

severe OSA pts compared to mild

pts and ctrls.

OSA pts and ctrls.

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11 normotensive

BRS calculated from ECG and

Spontaneous BRS was significantly lower

BRS is depressed in severe OSA

al.

pts with severe

continuous beat-to-beat BP recording

in severe OSA pts compared to ctrls

and this dysfunction may be involved

(1997) [44]

OSA; 10

during nocturnal sleep and wakefulness.

during sleep.

in the sympathetic overactivity

normotensive ctrls

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Parati G et

occurring during sleep.

10 OSA pts;

HR, continuous beat-to-beat BP, MSNA,

MSNA was higher during wakefulness in

et al.

10 ctrl;

PSG during wakefulness and sleep in

OSA pts compared to ctrls and obese

activity when awake with futher

(1995) [9]

5 obese ctrls

OSA pts and only during wakefulness in

ctrls. In OSA pts BP and MSNA did not

increases in sympathetic activity and

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SC

Somers VK

OSA pts have high sympathetic

ctrls and obese ctrls. In 4 OSA the same

fall during sleep. CPAP significantly

BP during sleep. These increases

measures were repeated after CPAP.

decreased BP and MSNA during sleep.

are attenuated by CPAP.

12 healthy

Before and after 2 weeks of nocturnal

Significant increase of SBP, DBP and

The repeated exposure to chronic

et al.

subjects

chronic intermittent hypoxia: 24-hour

MSNA and decrease of baroreflex control

intermittent hypoxia as occurred in

BP, MSNA and baroreflex control of

of sympathetic outflow after 2 weeks of

OSA causes a daytime BP elevation

sympathetic outflow during supine rest.

nocturnal chronic intermittent hypoxia.

and sympathetic overactivity.

HRV from continuous ECG recording

Progressively increases of LF and LF/HF

The study demonstrated sympathetic

during sleep.

during the apnoeic events.

activation during sleep apnoea

Vanninen E et al. (1996) [41]

12 OSA pts

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(2011) [54]

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Tamisier R

episodes.

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Table S2.

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Summary of articles included within the review on the association between narcolepsy type 1 and cardiovascular autonomic dysfunctions in humans. Abbreviations: BP: blood pressure; ctrls: controls; DBP: diastolic BP; ECG: electrocardiogram; hcrt-1: hypocretin-1; HF: high frequency; HR: heart rate; HRV:

PSG: polysomnography; pts: patients; SBP: systolic BP; VPSG: video PSG.

Subjects

Methods and Measures

Dauvilliers Y

14 NT1 pts; 14

Nocturnal PSG recording including

et al. (2011)

ctrls

ECG. HR changes before and after

36 NT1 pts (17

et al. (2012)

with hcrt-1

[121]

deficiency); 42 ctrls

24-hour ambulatory BP monitoring.

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Dauvilliers Y

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PLMS.

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[124]

Results

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Author

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heart rate variability; LF: low frequency; MSNA: muscle sympathetic nerve activity; NT1: narcolepsy type 1; PLMS: periodic limb movements during sleep;

Conclusions

NT1 pts compared to ctrls showed a

An attenuated HR response to PLMS

tachycardia of lower amplitude and a

was observed in NT1 pts suggesting

delayed and lower amplitude bradycardia

a lower sympathetic response related

associated with PLMS.

to hcrt-1 deficiency.

A significantly higher percentage of NT1

The study found a higher percentage

pts (30%) showed a non-dipper nocturnal

of non-dipper DBP in NT1 pts

DBP profile compared to ctrls (3%).

compared to ctrls.

Donadio V et

13 NT1 pts with

During nocturnal VPSG: BP, HR, skin

Skin sympathetic activity and MSNA

The study suggested that

al. (2014)

hcrt-1

sympathetic activity and MSNA.

showed changes during different sleep

sympathetic activity displays

[122]

deficiency; 5

stages in NT1 pts similar to ctrls

physiologic changes in NT1 pts

SBD, DBP and HR did not show the

during sleep, although these patients

ctrls

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showed a non-dipper BP profile.

DBP, HR and MSNA were significantly

The study showed lower sympathetic

Donadio V et

19 NT1 pts with

al. (2014a)

hcrt-1

lower in NT1 pts compared to ctrls during

activity during rest in NT1 compared

[130]

deficiency; 19

supine rest. Pearson regression analysis

to ctrls and suggested that this

ctrls

showed a significant correlation between

dysfunction may be correlated to

10 NT1 pts; 10

HRV from 48-hour ambulatory PSG

Strambi L et

ctrls

including also ECG.

hcrt-1 level and MSNA or HR.

hcrt-1 deficiency.

No difference in LF power was observed

The study showed a normal

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Ferini-

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MSNA, HR and BP during supine rest.

physiological decrease during sleep.

al. (1997)

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[131]

in NT1 and ctrls. HF power was

autonomic control of the

significantly reduced and LF/HF was

cardiovascular system during sleep

significantly higher in NT1 pts during

and an increased sympathetic-vagal

wakefulness before sleep compared to

balance during wakefulness

ctrls. No difference in HF power and

preceding sleep in NT1.

LF/HF was found during sleep.

15 NT1 pts with

HR, SBP, DBP, HRV and BP variability

HR, SBP, DBP did not differ between

The authors hypothesized a reduced

et al. (2008)

hcrt-1

during fasted resting state.

groups. Spectral power of HRV in all

sympathetic tone in NT1.

[129]

deficiency); 15

Grimaldi D et

10 NT1 pts (9

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ctrls

EP

Fronczek R

Continuous recording of SBP, DBP, HR

frequency bands and of BP variability was higher in NT1 pts compared to ctrls. LF/HF did not differ between groups. Changes of cardiovascular parameters

The study supported an enhanced

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with hcrt-1

and oro-nasal and abdominal breathing

during all tests in NT1 pts were

sympathetic HR modulation at rest in

[132]

deficiency); 18

during cardiovascular reflex tests

comparable to ctrls. LF/HF was

NT1 compared to ctrls.

ctrls

HRV was also calculated.

significantly increased during supine rest

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al. (2010)

in NT1 pts. LF and HF, expressed as

SC

normalized units, decreased in ctrls during head-up tilt test while they did not change

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in NT1 pts. Grimaldi D et

10 NT1 pts (9

Beat-to-beat SBP, DBP and HR during

NT1 pts showed daytime SBP and DBP

The study found a nocturnal BP non-

al. (2012)

with hcrt-1

24-hour PSG recording.

values comparable to ctrls. Nocturnal SBP

dipper profile and elevated HR

[120]

deficiency);

and DBP decrease was significantly lower

values in NT1 pts during sleep and

in NT1. 24-hour HR values were

wakefulness.

EP

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12 ctrls

9 NT1 pts (8

Beat-to-beat SBP, DBP and HR during

al. (2013)

with hcrt-1

[123]

Sorensen GL

to ctrls but nocturnal HR decline was similar in the two groups. Baroreflex sensitivity and cardiac vagal

The study suggested that autonomic

24-hour PSG recording.

modulation were significantly reduced in

control of cardiac variability is altered

deficiency);

HRV, BP variability and baroreflex

NT1 pts during wakefulness before sleep

in NT1 pts during wakefulness before

9 ctrls

sensitivity were also calculated.

compared to ctrls

sleep

67 NT1 (38 with

HR changes related to arousal and

HR response associated with arousal and

The study suggested a lower

AC C

Silvani A et

significantly higher in NT1 pts compared

ACCEPTED MANUSCRIPT

hcrt-1

isolated leg movements recorded during

isolated leg movements was significantly

sympathetic response to arousal and

(2013) [125]

deficiency; 46

nocturnal PSG.

lower in NT1 compared to ctrls. HR

isolated leg movements related to

with cataplexy;

response associated with arousal was

hcrt-1 deficiency.

23 with normal

significantly lower in NT1 pts with

hcrt-1 level);

cataplexy or hcrt-1 deficiency compared

22 ctrls

with NT1 pts with normal hcrt-1 level or

SC

RI PT

et al.

M AN U

without cataplexy 12 NT1 pts with

HR and HRV from nocturnal ambulatory

HR was significantly higher in NT1 pts in

The study showed elevated HR

Meijden WP

hcrt-1

PSG including ECG.

all sleep stages and during wakefulness

values in NT1 pts compared to

et al. (2015)

deficiency; 12

prior to sleep compared to ctrls. HR

controls during sleep and during

[128]

ctrls

increase in NT1 was independent of sleep

wakefulness prior to sleep

stage duration and sleep fragmentation

independent of sleep stage duration

HRV did not differ in the two groups

and sleep fragmentation, suggesting

AC C

EP

TE D

van der

a direct effect of hcrt-1 deficiency.

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